Current concepts of rheumatoid arthritis (RA) pathogenesis indicate that the disease is not caused by a single genetic defect, infection, or autoimmune reaction, but rather by improper control of host immune, inflammatory, and proliferative responses within the joints. This revised application for a Specialized Center for Research (SCOR) in RA focuses on this central theme. It contains four projects. Each concerns a molecular defect that may contribute to immune dysregulation and pannus formation in RA. Furthermore, each project aims to develop a therapeutic strategy to correct how bacterial and host-derived immunostimulatory DNA sequences can induce normal T1-type immune responses within the joints, and will demonstrate how ISS action might be interrupted therapeutically. Project 2: "The Synovium as an Immune Underprivileged Site" (Thomas J. Kipps, M.D. PhD. Project Leader) aims to delineate how the proteolytic environment within the joint prevents deletion of activated immune cells, and will devise gene therapeutic strategies to correct the defect. Project 3 "Immune Deviation Induced by Gene Vaccination: Applications to Arthritis" (Mary P. Corr, M.D. Project Leader) aims to deviate pro-inflammatory Th1 immune responses toward a less inflammatory Th2 phenotype by the creation of an "immunologic window" through genetic engineering of DNA vaccines. Project 4: "Properties of Shared Epitope-Specific T Cells in RA" (Salvatore Albani. M.D. Project Leader will discriminate the functional properties of isolated T cells from RA patients that recognize the shared epitope and will explore how pharmacological invention can change their frequency or function. The four projects will be supported by an Administrative Core (Dennis A. Carson, M.D. Director), that will coordinate the research and monitor its progress, and by a centralized Research Resources Core (Gary S. Firestein, M.D. Director), that will collect and distribute patient samples, and provide assistance with the evaluation of animal models. When completed, the experiments proposed in the SCOR will demonstrate how specific molecular abnormalities can promote the development of chronic arthritis, and will describe specific approaches for therapeutic intervention.